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Journal ArticleDOI

3,4,3',4'-Tetrachlorobiphenyl given to mice prenatally produces long-term decreases in striatal dopamine and receptor binding sites in the caudate nucleus

01 Mar 1981-Toxicology Letters (Elsevier)-Vol. 7, Iss: 6, pp 417-424
TL;DR: Mice exposed to TCB in utero had elevated levels of motor activity, which were associated with decreased DA levels and DA receptor binding sites, and these results indicate that in uterno exposure toTCB might permanently alter the development of striatal synapses.
About: This article is published in Toxicology Letters.The article was published on 1981-03-01 and is currently open access. It has received 94 citations till now. The article focuses on the topics: Striatum & Caudate nucleus.

Summary (2 min read)

INTRODUCTION

  • Mice exposed to TCB during gestation have been reported to exhibit a longlasting neurobehavioral syndrome consisting of stereotypic head movements, rotational behavior, increased motor activity, impaired neuromuscular strength and coordination, and learning deficits [1] .
  • Possible alterations in dopaminergic function were also suggested by the observation that haloperidol, a DA receptor antagonist, decreased the overall motor activity of mice exposed to TCB more than controls.
  • Mice exposed to TCB during gestation and showing signs of spinning at about 14 days of age were compared to non-spinning littermates also exposed in utero to TCB and to control animals whose mothers received corn oil vehicle.
  • The longest period at which TCB-exposed mice have been assessed is 8 months following birth [3] .
  • The present experiment extended this period of observation to 1 year postnatally in order to assess the irreversible nature of the neurological syndrome.

Subjects and prenatal exposure

  • Pregnant female CD-1 mice (Charles River, Wilmington, MA) were randomly assigned to test groups, caged individually and provided with free food and water.
  • Gas chromatographic/mass spectroscopic analysis of the TCB (synthesized at NIEHS, Research Triangle Park, NC) indicated a purity of 97.7%.
  • The day after birth, the young were counted and examined for gross abnormalities.
  • Littermates not exhibiting these behavioral characteristics were defined as 'non-spinners'.
  • The pups were housed with their natural mothers up to 21 days of age, after which they were rehoused according to exposure (corn oil or TCB), syndrome (spinner or non-spinner) and sex.

Body weights and activity measures

  • At one year of age, the mice were weighed and then tested for horizontally directed spontaneous motor activity.
  • Animals were placed individually into small plastic cages having the same dimensions as their home cage but not containing bedding and placed onto a commercially available activity monitor (Automex, Columbus Instruments; Columbus, OH) contained inside a sound-attenuated outer chamber equipped with a ventilation fan.

Neurochemica/ analyses

  • 2 weeks after being behaviorally tested, the mice were killed by decapitation and the brain quickly removed.
  • The corpus striatum was dissected [4] in an ice bath and frozen at -20°C until analysis.
  • Sample readings were corrected for blank values and counting efficiency by dividing the obtained value by the mg of protein per tissue to obtain µg of DA/g protein.
  • To determine the level of non-specific binding, half of the incubations were carried out in the presence of 10-6 M haloperidol.
  • Non-specific binding is always less than 200Jo of total binding.

Statistical analyses

  • Overall treatment effects on body weight, DA levels and DA binding were tested for statistical significance using a one-way ANOV A [8] .
  • Motor activity measures we.re expressed as rates per min, square-root transformed [9] and analyzed by ANOVA.
  • After significant overall effects were observed, differences between individual groups were tested for significance using Fisher's LSD Test [10] .

General health and body weights

  • ANOV A of the body weight data showed that there was a significant overall effect, F(2,21) = 3.89; P < 0.0364; pairwise comparisons between groups showed that the controls weighed significantly more than the TCB-exposed mice.
  • The TCB spinners and non-spinners did not differ statistically.
  • With the exception that the TCB non-spinners had lower body weights than controls, these observations are consistent with those of Chou et al. [13] .

Motor activity

  • Pairwise comparisons of the groups revealed that the TCB spinners were significantly more active than the controls (Fig. 1 ).
  • The TCB nonspinners had higher activity scores than the controls, but the difference was not statistically significant.
  • The TCB non-spinners also did not differ statistically from the TCB spinners.

Effects on the striatal dopamine system

  • Pairwise comparisons between groups showed that the DA levels of the TCB spinners were significantly less than those of the controls (Fig. 2A ).
  • The DA levels of the TCB non-spinners were significantly higher than the TCB spinners.
  • Pairwise comparisons between groups showed that the specific binding for [3H]spiroperidol was significantly decreased in the corpus striatum of both TCB non-spinners and TCB spinners (Fig. 2B ).
  • The neurochemical data indicate that in utero exposure to TCB can produce significant alterations in the levels and specific binding sites of DA in the corpus striatum of mice.
  • Significant alterations in DA binding were also observed in mice not exhibiting the spinning syndrome.

DISCUSSION

  • The results of these experiments indicate that in utero exposure to TCB, an isomer present in some PCB mixtures, may produce a significant hyperactivity in exposed animals for up to 1 year after birth.
  • Chou and his coworkers [3] have proposed that developmental exposure to TCB might interfere with the synaptogenesis of DA neurons and might, in part, account for the spinning and hyperactivity of the TCB-exposed animals.
  • Once initiated, the spinning typically was unidirectional; no one direction (left or right) appeared to predominate, however.
  • The simultaneous depression of both DA levels and the extent of spiroperidol binding suggest that the normal ontogenesis of DA neurons was impaired.
  • This might account for the excess activity of treated animals.

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Citations
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01 Nov 2000
TL;DR: A toxicological profile for PCBs, Draft for Public Comment, was released in December 1998 as discussed by the authors, which supercedes any previously released draft or final profile, but no less than once every three years.
Abstract: DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. A toxicological Profile for PCBs, Draft for Public Comment, was released in December 1998. This edition supercedes any previously released draft or final profile. Toxicological profiles are revised and republished as necessary, but no less than once every three years. The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public law 99-499) which amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed ATSDR to prepared toxicological profiles for hazardous substances most commonly found at facilities on the CERCLA National Priorities List and that pose the most significant potential threat to human health, as determined by ATSDR and the EPA. The availability of the revised priority list of 275 hazardous substances was announced in the Administrator of ATSDR to prepare a toxicological profile for each substance on the list. Toxicological Profiles are a unique compilation of toxicological information on a given hazardous substance. Each profile reflects a comprehensive and extensive evaluation, summary, and interpretation of available toxicologic and epidemiologic information on a substance. Health care providers treating patients potentially exposed to hazardous substances will find the following information helpful for fast answers to often-asked questions. Chapter 1: Public Health Statement: The Public Health Statement can be a useful tool for educating patients about possible exposure to a hazardous substance. It explains a substance's relevant toxicologic properties in a nontechnical, question-and-answer format, and it includes a review of the general health effects observed following exposure. Chapter 3: Health Effects: Specific health effects of a given hazardous compound are reported by type of health effect (death, systemic, immunologic, reproductive), by route of exposure, and by length of exposure (acute, intermediate, and chronic). In addition, both human and animal studies are reported in this section. NOTE: Not all health effects reported in this section are necessarily observed in the clinical setting. Please refer to the Public Health Statement to identify general health effects observed following exposure. The following additional material can be ordered through the ATSDR Information Center: Case Studies in Environmental Medicine: Taking an Exposure History—The importance of taking an exposure history and how to conduct one are described, and an example of a thorough exposure history is provided. Other …

660 citations


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  • ...Mice exposed to 3,3',4,4'-tetraCB (PCB 77) in utero (maternal dose 32 mg/kg/day), which exhibited spinning behavior and hyperactivity at 1 year of age, had decreased dopamine levels and dopamine receptor binding sites in the corpus striatum (Agrawal et al. 1981)....

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501 citations


Cites background from "3,4,3',4'-Tetrachlorobiphenyl given..."

  • ...In vivo studies with mice (11), rats and monkeys (12) also show reduced levels of dopamine in the brains of exposed animals....

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TL;DR: Recent developments in the toxic equivalency factor (TEF) approach for the assessment of toxic effects due to dioxin-like PCBs have been examined and relative merits and implications of using TEF and total PCB approaches for assessing the potential for toxic effects in wildlife was examined.
Abstract: Polychlorinated biphenyls (PCBs) are persistent, bioaccumulative and toxic contaminants in the environment. Individual PCB congeners exhibit different physico-chemical properties and biological activities which result in different environmental distributions and toxicity profiles. The variable composition of PCB residues in environmental matrices and their different mechanisms of toxicity, complicate the development of scientifically based regulations for the risk assessment. Various approaches for the assessment of risks of PCBs have been critically examined. Recent developments in the toxic equivalency factor (TEF) approach for the assessment of toxic effects due to dioxin-like PCBs have been examined. PCB exposure studies which describe non-dioxin-like toxic effects, particularly neuro-behavioral effects and their effective doses in animals were also considered. A comparative assessment of effective doses for dioxin-like and non-dioxin-like effects by PCBs was made to evaluate the relative significance of non-ortho and ortho-substituted PCBs in risk assessment. Using mink as an example, relative merits and implications of using TEF and total PCB approaches for assessing the potential for toxic effects in wildlife was examined.

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References
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Journal Article
TL;DR: Procedures are described for measuring protein in solution or after precipitation with acids or other agents, and for the determination of as little as 0.2 gamma of protein.

289,852 citations

Journal ArticleDOI
TL;DR: It is revealed that norepinephrine and dopamine are specifically localized in complex systems of neurons in the brain, a finding which lends support to the hypothesis that both amines may be neurotransmitters in the central nervous system.
Abstract: NOREPINEPHRINE is found in appreciable amounts in mammalian brain tissue. VOGT (1954) showed that this amine was unequally distributed in various regions of the cat brain, the highest concentrations being found in the hypothalamus. Similar findings were reported for other animal species (BERTLER and ROSENGREN, 1959a; MCGEER, MCGEER and WADA, 1963) and man (SANO, GAMO, KAKIMOTO, TANAGUCHI, TAKE~ADA and NISHINUMA, 1959). Dopamine is also present in the brain in comparable amounts to norepinephrine (MONTAGU, 1957 ; CARLSSON, LINDQVIST, MAGNUSSON and WALDECK, 1958) but with a different regional distribution, the highest concentrations being in the corpus striatum of both animals and man (BERTLER and ROSENGREN, 1959a; SANO et al., 1959; EHRINGER and HORNYKIEWICZ, 1960; BERTLER, 1961). The anatomical distribution of these two catecholamines in the brain was confirmed by the use of fluorescent histochemical techniques which allow a precise description of the cellular localization of the amines in brain tissue (CARLSSON, FALK and HILLARP, 1962; DAHLSTROM and FUXE, 1964; FUXE, 1965). These techniques revealed that norepinephrine and dopamine are specifically localized in complex systems of neurons in the brain, a finding which lends support to the hypothesis that both amines may be neurotransmitters in the central nervous system. The metabolism of catecholamines in the rat brain was studied by introducing small amounts of radioactive norepinephrine or dopamine directly into the lateral ventricle (MILHAUD and GLOWINSKI, 1962, 1963; GLOWINSKI, KOPIN and AXELROD, 1965; GLOWINSKI, IVERSEN and AXELROD, 1966). By this approach the blood-brain barrier to catecholamines can be circumvented, penetration of the radioactive catecholamines into the brain being allowed. The disposition of PHInorepinephrine in the whole brain indicates that [3H]norepinephrine introduced into the lateral ventricle of the brain mixes with the endogenous amine and can be used as a tracer to study the biochemical behaviour of norepinephrine in the brain (GLOWINSKI and AXELROD, 1966). PHIDopamine, which is also taken up and retained in the brain, is rapidly metabolized and converted to norepinephrine (GLOWINSKI et a!., 1966). The unequal regional distribution of the endogeneous catecholamines in the brain led us to undertake a study of the disposition of radioactive norepinephrine and dopamine in various brain regions after intraventricular injection. The regional

5,385 citations

Book
01 Jan 1966
TL;DR: In this article, the authors presented a case of two means regression method for the family error rate, which was used to estimate the probability of a family having a nonzero family error.
Abstract: 1 Introduction.- 1 Case of two means.- 2 Error rates.- 2.1 Probability of a nonzero family error rate.- 2.2 Expected family error rate.- 2.3 Allocation of error.- 3 Basic techniques.- 3.1 Repeated normal statistics.- 3.2 Maximum modulus (Tukey).- 3.3 Bonferroni normal statistics.- 3.4 ?2 projections (Scheffe).- 3.5 Allocation.- 3.6 Multiple modulus tests (Duncan).- 3.7 Least significant difference test (Fisher).- 4 p-mean significance levels.- 5 Families.- 2 Normal Univariate Techniques.- 1 Studentized range (Tukey).- 1.1 Method.- 1.2 Applications.- 1.3 Comparison.- 1.4 Derivation.- 1.5 Distributions and tables.- 2 F projections (Scheffe)48.- 2.1 Method.- 2.2 Applications.- 2.3 Comparison.- 2.4 Derivation.- 2.5 Distributions and tables.- 3 Bonferroni t statistics.- 3.1 Method.- 3.2 Applications.- 3.3 Comparison.- 3.4 Derivation.- 3.5 Distributions and tables.- 4 Studentized maximum modulus.- 4.1 Method.- 4.2 Applications.- 4.3 Comparison.- 4.4 Derivation.- 4.5 Distributions and tables.- 5 Many-one t statistics76.- 5.1 Method.- 5.2 Applications.- 5.3 Comparison.- 5.4 Derivation.- 5.5 Distributions and tables.- 6 Multiple range tests (Duncan).- 6.1 Method.- 6.2 Applications.- 6.3 Comparison.- 6.4 Derivation.- 6.5 Distributions and tables.- 7 Least significant difference test (Fisher).- 7.1 Method.- 7.2 Applications.- 7.3 Comparison.- 7.4 Derivation.- 7.5 Distributions and tables.- 8 Other techniques.- 8.1 Tukey's gap-straggler-variance test.- 8.2 Shortcut methods.- 8.3 Multiple F tests.- 8.4 Two-sample confidence intervals of predetermined length.- 8.5 An improved Bonferroni inequality.- 9 Power.- 10 Robustness.- 3 Regression Techniques.- 1 Regression surface confidence bands.- 1.1 Method.- 1.2 Comparison.- 1.3 Derivation.- 2 Prediction.- 2.1 Method.- 2.2 Comparison.- 2.3 Derivation.- 3 Discrimination.- 3.1 Method.- 3.2 Comparison.- 3.3 Derivation.- 4 Other techniques.- 4.1 Linear confidence bands.- 4.2 Tolerance intervals.- 4.3 Unlimited discrimination intervals.- 4 Nonparametric Techniques.- 1 Many-one sign statistics (Steel).- 1.1 Method.- 1.2 Applications.- 1.3 Comparison.- 1.4 Derivation.- 1.5 Distributions and tables.- 2 k-sample sign statistics.- 2.1 Method.- 2.2 Applications.- 2.3 Comparison.- 2.4 Derivation.- 2.5 Distributions and tables.- 3 Many-one rank statistics (Steel).- 3.1 Method.- 3.2 Applications.- 3.3 Comparison.- 3.4 Derivation.- 3.5 Distributions and tables.- 4 k-sample rank statistics.- 4.1 Method.- 4.2 Applications.- 4.3 Comparison.- 4.4 Derivation.- 4.5 Distributions and tables.- 5 Signed-rank statistics.- 6 Kruskal-Wallis rank statistics (Nemenyi).- 6.1 Method.- 6.2 Applications.- 6.3 Comparison.- 6.4 Derivation.- 6.5 Distributions and tables.- 7 Friedman rank statistics (Nemenyi).- 7.1 Method.- 7.2 Applications.- 7.3 Comparison.- 7.4 Derivation.- 7.5 Distributions and tables.- 8 Other techniques.- 8.1 Permutation tests.- 8.2 Median tests (Nemenyi).- 8.3 Kolmogorov-Smirnov statistics.- 5 Multivariate Techniques.- 1 Single population covariance scalar unknown.- 1.1 Method.- 1.2 Applications.- 1.3 Comparison.- 1.4 Derivation.- 1.5 Distributions and tables.- 2 Single population covariance matrix unknown.- 2.1 Method.- 2.2 Applications.- 2.3 Comparison.- 2.4 Derivation.- 2.5 Distributions and tables.- 3 k populations covariance matrix unknown.- 3.1 Method.- 3.2 Applications.- 3.3 Comparison.- 3.4 Derivation.- 3.5 Distributions and tables.- 4 Other techniques.- 4.1 Variances known covariances unknown.- 4.2 Variance-covariance intervals.- 4.3 Two-sample confidence intervals of predetermined length.- 6 Miscellaneous Techniques.- 1 Outlier detection.- 2 Multinomial populations.- 2.1 Single population.- 2.2 Several populations.- 2.3 Cross-product ratios.- 2.4 Logistic response curves.- 3 Equality of variances.- 4 Periodogram analysis.- 5 Alternative approaches: selection, ranking, slippage.- A Strong Law For The Expected Error Rate.- B TABLES.- I Percentage points of the studentized range.- II Percentage points of the Bonferroni t statistic.- III Percentage points of the studentized maximum modulus.- IV Percentage points of the many-one t statistics.- V Percentage points of the Duncan multiple range test.- VI Percentage points of the many-one sign statistics.- VIII Percentage points of the many-one rank statistics.- IX Percentage points of the k-sample rank statistics.- Developments in Multiple Comparisons 1966-).- 3.5 Allocation.- 3.6 Multiple modulus tests (Duncan).- 3.7 Least significant difference test (Fisher).- 4 p-mean significance levels.- 5 Families.- 2 Normal Univariate Techniques.- 1 Studentized range (Tukey).- 1.1 Method.- 1.2 Applications.- 1.3 Comparison.- 1.4 Derivation.- 1.5 Distributions and tables.- 2 F projections (Scheffe)48.- 2.1 Method.- 2.2 Applications.- 2.3 Comparison.- 2.4 Derivation.- 2.5 Distributions and tables.- 3 Bonferroni t statistics.- 3.1 Method.- 3.2 Applications.- 3.3 Comparison.- 3.4 Derivation.- 3.5 Distributions and tables.- 4 Studentized maximum modulus.- 4.1 Method.- 4.2 Applications.- 4.3 Comparison.- 4.4 Derivation.- 4.5 Distributions and tables.- 5 Many-one t statistics76.- 5.1 Method.- 5.2 Applications.- 5.3 Comparison.- 5.4 Derivation.- 5.5 Distributions and tables.- 6 Multiple range tests (Duncan).- 6.1 Method.- 6.2 Applications.- 6.3 Comparison.- 6.4 Derivation.- 6.5 Distributions and tables.- 7 Least significant difference test (Fisher).- 7.1 Method.- 7.2 Applications.- 7.3 Comparison.- 7.4 Derivation.- 7.5 Distributions and tables.- 8 Other techniques.- 8.1 Tukey's gap-straggler-variance test.- 8.2 Shortcut methods.- 8.3 Multiple F tests.- 8.4 Two-sample confidence intervals of predetermined length.- 8.5 An improved Bonferroni inequality.- 9 Power.- 10 Robustness.- 3 Regression Techniques.- 1 Regression surface confidence bands.- 1.1 Method.- 1.2 Comparison.- 1.3 Derivation.- 2 Prediction.- 2.1 Method.- 2.2 Comparison.- 2.3 Derivation.- 3 Discrimination.- 3.1 Method.- 3.2 Comparison.- 3.3 Derivation.- 4 Other techniques.- 4.1 Linear confidence bands.- 4.2 Tolerance intervals.- 4.3 Unlimited discrimination intervals.- 4 Nonparametric Techniques.- 1 Many-one sign statistics (Steel).- 1.1 Method.- 1.2 Applications.- 1.3 Comparison.- 1.4 Derivation.- 1.5 Distributions and tables.- 2 k-sample sign statistics.- 2.1 Method.- 2.2 Applications.- 2.3 Comparison.- 2.4 Derivation.- 2.5 Distributions and tables.- 3 Many-one rank statistics (Steel).- 3.1 Method.- 3.2 Applications.- 3.3 Comparison.- 3.4 Derivation.- 3.5 Distributions and tables.- 4 k-sample rank statistics.- 4.1 Method.- 4.2 Applications.- 4.3 Comparison.- 4.4 Derivation.- 4.5 Distributions and tables.- 5 Signed-rank statistics.- 6 Kruskal-Wallis rank statistics (Nemenyi).- 6.1 Method.- 6.2 Applications.- 6.3 Comparison.- 6.4 Derivation.- 6.5 Distributions and tables.- 7 Friedman rank statistics (Nemenyi).- 7.1 Method.- 7.2 Applications.- 7.3 Comparison.- 7.4 Derivation.- 7.5 Distributions and tables.- 8 Other techniques.- 8.1 Permutation tests.- 8.2 Median tests (Nemenyi).- 8.3 Kolmogorov-Smirnov statistics.- 5 Multivariate Techniques.- 1 Single population covariance scalar unknown.- 1.1 Method.- 1.2 Applications.- 1.3 Comparison.- 1.4 Derivation.- 1.5 Distributions and tables.- 2 Single population covariance matrix unknown.- 2.1 Method.- 2.2 Applications.- 2.3 Comparison.- 2.4 Derivation.- 2.5 Distributions and tables.- 3 k populations covariance matrix unknown.- 3.1 Method.- 3.2 Applications.- 3.3 Comparison.- 3.4 Derivation.- 3.5 Distributions and tables.- 4 Other techniques.- 4.1 Variances known covariances unknown.- 4.2 Variance-covariance intervals.- 4.3 Two-sample confidence intervals of predetermined length.- 6 Miscellaneous Techniques.- 1 Outlier detection.- 2 Multinomial populations.- 2.1 Single population.- 2.2 Several populations.- 2.3 Cross-product ratios.- 2.4 Logistic response curves.- 3 Equality of variances.- 4 Periodogram analysis.- 5 Alternative approaches: selection, ranking, slippage.- A Strong Law For The Expected Error Rate.- B TABLES.- I Percentage points of the studentized range.- II Percentage points of the Bonferroni t statistic.- III Percentage points of the studentized maximum modulus.- IV Percentage points of the many-one t statistics.- V Percentage points of the Duncan multiple range test.- VI Percentage points of the many-one sign statistics.- VIII Percentage points of the many-one rank statistics.- IX Percentage points of the k-sample rank statistics.- Developments in Multiple Comparisons 1966-1976.- 1 Introduction.- 2 Papers of special interest.- 2.1 Probability inequalities.- 2.2 Methods for unbalanced ANOVA.- 2.3 Conditional confidence levels.- 2.4 Empirical Bayes approach.- 2.5 Confidence bands in regression.- 3 References.- 4 Bibliography 1966-1976.- 4.1 Survey articles.- 4.2 Probability inequalities.- 4.3 Tables.- 4.4 Normal multifactor methods.- 4.5 Regression.- 4.6 Categorical data.- 4.7 Nonparametric techniques.- 4.8 Multivariate methods.- 4.9 Miscellaneous.- 4.10 Pre-1966 articles missed in [6].- 4.11 Late additions.- 5 List of journals scanned.- Addendum New Table of the Studentized Maximum Modulus.- Table IIIA Percentage points of the studentized maximum modulus.- Author Index.

4,763 citations

Journal ArticleDOI
05 Aug 1977-Science
TL;DR: The binding of [3H]haloperidol to rat striatal dopamine receptors increases after lesion (made by injection of 6-hydroxydopamine) of the nigrostriatal dopamine pathway in those rats which are behaviorally supersensitive, as reflected by apomorphine-induced contralateral rotations.
Abstract: The binding of [3H]haloperidol to rat striatal dopamine receptors increases after lesion (made by injection of 6-hydroxydopamine) of the nigrostriatal dopamine pathway in those rats which are behaviorally supersensitive, as reflected by apomorphine-induced contralateral rotations. The enhanced binding is associated with an increased number of receptor sites with no change in their affinity.

714 citations

Journal ArticleDOI
TL;DR: It is not yet clear whether the relation between the length of treatment and the persistence of supersensitivity holds for very long treatments but in principle the relationship might account forThe persistence of tardive dyskinesia after years of neuroleptic pretreatment.
Abstract: It is known that a single dose of a neuroleptic can elicit dopaminergic supersensitivity in animals. On the other hand, the clinical syndrome of tardive dyskinesia takes many months of years to develop. To resolve this apparent discrepancy, it is possible that subclinical or latent tardive dyskinesia is fully compensated in most patients taking neuroleptics. In others, where the tardive dyskinesia is full-blown and grossly apparent, the dopaminergic supersensitivity may be decompensated. Such compensatory and decompensatory phases have been proposed earlier by Hornykiewicz (1974), in the case of Parkinson's Disease. Dopaminergic supersensitivity persists for a period proportional to the lenght of the neuroleptic treatment. It is not yet clear whether the relation between the length of treatment and the persistence of supersensitivity holds for very long treatments, but in principle the relationship might account for the persistence of tardive dyskinesia after years of neuroleptic pretreatment.

260 citations